The cause of human lupus remains unknown. Work from our group performed over the last 16 years suggests that changes in T cell gene expression, caused by hypomethylation of crucial regulatory regions, contributes to the initiation of some forms of drug-induced lupus as well as idiopathic human lupus. More recent work demonstrates that levels of the enzymes mediating T cell DNA methylation are decreased in T cells from patients with lupus, and that the decreased levels are due to decreased signaling through the ras-MAPK (ERK) pathway. Further, inhibiting ERK pathway signaling in normal human T cells causes DNA hypomethylation and changes in T cell function and gene expression resembling those in our hypomethylation models and in idiopathic SLE. Finally, inhibiting ERK pathway signaling in murine models induces a lupus-like disease. We hypothesize that abnormally decreased T cell ERK pathway signaling contributes to the development of lupus through effects on DNA methylation and the expression of methylation sensitive genes. This hypothesis will be tested in the following specific aims: 1) Compare the effects of ERK pathway inhibitors and DNA Mtase inhibitors on the methylation status and expression of selected methylation sensitive T cell genes, and on T cell function, 2) Determine if decreased T cell ERK pathway signaling and overexpression of methylation sensitive genes identified in aim 1 contribute to autoimmunity using murine models, 3) Determine if the same genes are hypomethylated and overexpressed in human lupus T cells, and 4) Identify the defect causing decreased ERK pathway signaling in human lupus T cells. We anticipate that these studies will provide new insights into mechanisms causing lupus-like illnesses, and identify new approaches to the treatment of this sometimes fatal disease.